Cachexia, or disease wasting, confers a poor prognosis in a variety of advanced disease states including chronic kidney disease, congestive heart failure, cancer, AIDS, and chronic obstructive pulmonary disease. Patients afflicted by this syndrome are characterized by decreased caloric intake, decreased lean body mass and increased basal metabolic rate that cannot be corrected by increased caloric intake. The melanocortin 4 receptor (MC4R), a seven transmembrane domain receptor, plays a critical role in regulating food intake and energy expenditure. Animal models of cachexia are protected against the anorexic symptoms of cachexia following genetic deletion of the MC4R or pharmacological inhibition by its endogenous inverse agonist, AgRP. AgRP blocks binding of the endogenous MC4R agonist, ?-MSH, and ?-MSH mediated activation of the G?s- adenylyl cyclase-cAMP signaling pathway. Interestingly, even high affinity synthetic antagonists of the MC4R are not as efficacious as AgRP in stimulating food intake and blocking cachexia. Recently, our group has discovered that AgRP is actually a biased agonist of the MC4R. Instead of simply competing with ?-MSH for receptor occupancy, AgRP binding to MC4R leads to the opening of the inward rectifying potassium channel Kir7.1. This finding is particularly interesting given the unique orexigenic effects of AgRP. A single dose of AgRP can stimulate 24hr food intake for up to one week. Furthermore, AgRP but not synthetic MC4R antagonists can potently stimulate food intake in cachexic mice for up to 24 hours following administration. In this study we will examine the rank order of activity of a variety of AgRP analogs and synthetic MC4R antagonists in coupling the MC4R to Kir7.1 in a cell culture model, and in stimulation of food intake and inhibition of disease cachexia. Similarly, we will compare the response of WT and MC4R specific Kir7.1 knockout mice to a tumor cachexia challenge. Together, these studies will rigorously test the hypothesis that the MC4R-Kir7.1 signaling pathway is critical for the efficacy of AgRP in stimulation of feeding and blockade of disease cachexia. If this hypothesis is correct, this will, in turn, validate a novel drug discovery path for the development of potent anti-cachexigenic agents.